Cilostazol, 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, shown below, is a cyclic AMP phosphodiesterase III inhibitor.

Cilostazol is a white to off white crystalline powder that is slightly soluble in methanol and ethanol, but is practically insoluble in water, 0.1N HCl and 0.1N NaOH. Cilostazol is further described at Monograph no. 2298 of the Merck Index (Thirteenth Edition, 2001) and is also identified by CAS Registry Number: 73963-72-1. Preparation of cilostazol is described by Nishi et al. in Chem. Pharm. Bull. 31, 1151 (1983) and in U.S. Pat. No. 4,277,479.
Cilostazol exhibits high inhibitory action for platelet aggregation as well as phosphodiesterase inhibition, antiulcer activity, hypotensive action, antiphlogistic action, anti-inflammatory action, etc. As an anti-platelet agent, a vasodilator, phosphodiesterase inhibitor, and a platelet aggregation inhibitor cilostazol has been shown to be an effective drug for the prevention and treatment of ischemic symptoms caused by chronic arterial occlusion such as intermittent claudication. Cilostazol has efficacy for improving various ischemic conditions such as ulcer, pain and coldness that are based on chronic arterial occlusion. Although its mechanism of action is not entirely clear, cilostazol inhibits phosphodiesterase III and suppresses cAMP degradation. These events result in increased levels of cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation. In addition to its reported vasodilator and anti-platelet effects, cilostazol reduces the ability of blood to clot and has been proposed to have beneficial effects on plasma lipoproteins. By inhibiting the blood platelets from coagulating or aggregating, blood flow is enhanced and increased. Cilostazol has also been approved as a medicament having an indication for improving cerebral circulation which prevents the relapse after treatment of cerebral infarction (except cardiogenic cerebral infarction) (JP-A-56 (1981)-49378).
Cilostazol and its various uses have been described in U.S. Pat. No. 4,277,479, “Tetrazolylalkoxycarbostyril Derivatives and Pharmaceutical Compositions Containing Them”; U.S. Pat. No. 6,187,790, “Use of Cilostazol for Treatment of Sexual Dysfunction”; U.S. Pat. No. 6,515,128, “Processes for Preparing Cilostazol”; U.S. Pat. Nos. 6,531,603, 6,573,382, 6,531,603, 6,657,061, and 6,660,864, “Polymorphic Forms of 6-[4-1(1-Cyclohexyl-1H-tetrazol-5-yl)Butoxy]-3,4-Dihydro-2(1H)-Quinolinone”; U.S. Pat. Nos. 6,525,201, 6,660,773, and 6,740,758, “Processes for Preparing 6-Hydroxy-3,4-Dihydroquinolinone, Cilostazol and N-(4-Methoxyphenyl)-3-Chloropropionamide”, and U.S. Pat. No. 6,825,214, “Substantially Pure Cilostazol and Processes for Making Same.” Formulations of cilostazol and their therapeutic uses are disclosed, for example, in WO 2009/113,741; WO 2009/107,864; and U.S. Published application US 2009/0297596. All of these documents are incorporated herein by reference.
Cilostazol is marketed as 50 mg and 100 mg tablets by Otsuka Pharmaceutical Co., Ltd under the PLETAL® tradename. Cilostazol is classified by the Biopharmaceutical Classification System (BCS) as a Class II drug, indicating that it is a low solubility, high permeability drug. This signifies that the rate limiting step for oral bioavailability of cilostazol is the dissolution of the drug from its pharmaceutical dosage form.
Although therapeutic efficacy is the primary concern for an active pharmaceutical ingredient (API), the salt and solid state form (i.e., the crystalline or amorphous form) of a drug candidate can be critical to its pharmacological properties, such as bioavailability, and to its development as a viable API. Recently, crystalline forms of API's have been used to alter the physicochemical properties of a particular API. Each crystalline form of a drug candidate can have different solid state (physical and chemical) properties. The differences in physical properties exhibited by a novel solid form of an API (such as a cocrystal or polymorph of the original therapeutic compound) affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and solubility and dissolution rates (important factors in determining bioavailability). Because these practical physical properties are influenced by the solid state properties of the crystalline form of the API, they can significantly impact the selection of a compound as an API, the ultimate pharmaceutical dosage form, the optimization of manufacturing processes, and absorption in the body. Moreover, finding the most adequate solid state form for further drug development can reduce the time and the cost of that development.
Obtaining crystalline forms of an API is extremely useful in drug development. It permits better characterization of the drug candidate's chemical and physical properties. It is also possible to achieve desired properties of a particular API by forming a cocrystal of the API and a coformer. Crystalline forms often have better chemical and physical properties than the free base in its amorphous state. Such crystalline forms may, as with the cocrystals of the invention, possess more favorable pharmaceutical and pharmacological properties or be easier to process than known forms of the API itself. For example, a cocrystal may have different dissolution and solubility properties than the API itself and can be used to deliver APIs therapeutically. New drug formulations comprising cocrystals of a given API may have superior properties over its existing drug formulations. They may also have better storage stability.
Another potentially important solid state property of an API is its dissolution rate in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it impacts the rate at which an orally administered active ingredient may reach the patient's bloodstream.
A cocrystal of an API is a distinct chemical composition of the API and a coformer which generally possesses distinct crystallographic and spectroscopic properties when compared to those of the API and coformer individually. Crystallographic and spectroscopic properties of crystalline forms are typically measured by X-ray powder diffraction (XRPD) and single crystal X-ray crystallography, among other techniques. Cocrystals often also exhibit distinct thermal behavior. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC).